Direct fluorination of organic compounds must be carried out under suitable conditions to control the aggressive reaction of elemental fluorine. The present invention is directed to the placing of elemental fluorine in the 2-ring position of substituted pyridines.
Simons (U.S. Pat. No. 2,447,717) recommended pyridine as a reaction medium for direct fluorination of various organic compounds, including toluene, benzene, acetic acid and others. He speculated that fluorine complexes with pyridine and becomes a fluorinating agent for other organic compounds. Simons does indicate that pyridine can form 2-fluoropyridine when no other organic compound is present. Methyl pyridine is mentioned as an alternative material which can be used as a reaction medium, but direct fluorination of that compound is not discussed.
Alkyl substituted pyridines can be fluorinated in the 2-ring position by replacing another substituent already located there. The Schiemann reaction replaces an amino group at the 2-ring position with a fluorine atom. Another approach begins with a chlorine atom at the 2-ring posirion and replaces it with fluorine supplied by KHF.sub.2 according to Boudakian, J. Heterocyclic Chem.. 1967, 4,381 or by NaF according to Finger and Starr, J. Am Chem Soc, Vol. 81, pp. 2674-2675.
The direct fluorination of alkyl-substituted pyridines has not been given much attention in the art. The corresponding reaction of chlorine with alkyl pyridines has been studied by McBee (Ind. Eng. Chem., 1947, 39, 389 and others). When an alkyl group is present, it is chlorinated first and only when rigorous conditions are employed is chlorine introduced into the ring. Thus, while chlorine will react with pyridine to give 2-chloropyridine, if methyl pyridine is used, the product is trichloromethyl pyridine. As will be seen, these results are in striking contrast with the results obtained in the fluorination of alkyl pyridines.
More generally, the halogenation of pyridines has been discussed by Mosher in Heterocyclic Compounds, Vol. I, ed R. C. Elderfield, Chap. 8, p. 509, John Wiley, 1950. Mosher states that while pyridine derivatives with ortho or para-directing groups (i.e. OCOCH.sub.3, NHR) have been directly substituted, that where meta-directing groups (i.e. CN, COOR, COR, NO ) are present, halogenation is not expected. As previously discussed, Mosher indicates that with the picolines chlorine reacts with the methyl group and not with the nucleus until the methyl group has been fully chlorinated. From this discussion, one skilled in the art could expect that fluorine would not react with the nucleus and instead would prefer to react with alkyl substituted groups.
Since 2-fluoro pyridines are useful chemical intermediates, it would be desirable to be able to directly fluorinate substituted pyridines in the 2-ring position. Unexpectedly, the present inventors have found that under mild reaction conditions such a reaction is possible.